Ciprofol Ameliorates Myocardial Ischemia/Reperfusion Injury by Inhibiting Ferroptosis Through Upregulating HIF-1α

Drug Des Devel Ther. 2024 Dec 18:18:6115-6132. doi: 10.2147/DDDT.S480514. eCollection 2024.

Abstract

Purpose: Ciprofol is a novel intravenous anesthetic that has been increasingly used in clinical anesthesia and sedation. Studies suggested that ciprofol reduced oxidative stress and inflammatory responses to alleviate cerebral ischemia/reperfusion (I/R) injury, but whether ciprofol protects the heart against I/R injury and the mechanisms are unknown. Herein, we assessed the effects of ciprofol on ferroptosis during myocardial I/R injury.

Methods: Experimental models of myocardial I/R injury in mice (ischemia for 30 min and reperfusion for 24 h) and hypoxia/reoxygenation (H/R) injury in H9c2 cardiomyocytes (hypoxia for 6 h followed by 6 h of reoxygenation) were established. Ciprofol was used prior to ischemia or hypoxia. Echocardiography, myocardial TTC staining, HE staining, DAB-enhanced Perl's staining, transmission electron microscopy, FerroOrange staining, Liperfluo staining, JC-1 staining, Rhodamine-123 staining, DCFH-DA staining, and Western blot were performed. Cell viability, serum cardiac enzymes, and oxidative- and ferroptosis-related biomarkers were measured. HIF-1α siRNA transfection and the specific inhibitor BAY87-2243 were utilized for mechanistic investigation.

Results: Ciprofol treatment reduced myocardial infarct area and myocardium damage, alleviated oxidative stress and mitochondrial injury, suppressed Fe2+ accumulation and ferroptosis, and improved cardiac function in mice with myocardial I/R injury. Ciprofol also increased cell viability, attenuated mitochondrial damage, and reduced intracellular Fe2+ and lipid peroxidation in cardiomyocytes with H/R injury. Ciprofol enhanced the protein expression of HIF-1α and GPX4 and reduced the expression of ACSL4. Specifically, the protective effects of ciprofol against I/R or H/R injury were abolished by downregulating the expression of HIF-1α using siRNA transfection or the inhibitor BAY87-2243.

Conclusion: Ciprofol ameliorated myocardial I/R injury in mice and H/R injury in cardiomyocytes by inhibiting ferroptosis via the upregulation of HIF-1α expression.

Keywords: GPX4/ACSL4; HIF-1α; ciprofol; ferroptosis; myocardial ischemia/reperfusion injury; oxidative stress.

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cyclopropanes
  • Dose-Response Relationship, Drug
  • Ferroptosis* / drug effects
  • Hypoxia-Inducible Factor 1, alpha Subunit* / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Myocardial Reperfusion Injury* / drug therapy
  • Myocardial Reperfusion Injury* / metabolism
  • Myocardial Reperfusion Injury* / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oxidative Stress / drug effects
  • Rats
  • Up-Regulation* / drug effects

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hif1a protein, mouse
  • (2-(1R)-1-cyclopropyl)ethyl-6-isopropyl-phenol
  • Cyclopropanes